Vitamin D and Chronic Pain: Promising Correlates

How we think about the etiology and treatment of chronic
pain varies considerably depending on the type or description of pain,
the history of injury or metabolic disorder, the site of pain, what
makes it better or worse, and the age of the patient. In primary care,
we frequently determine a vitamin B12 level for patients with neuropathy, and we know that replacing or repleting B12
can potentially reverse neuropathic pain. Similarly, in patients
presenting with depression, a thyroid-stimulating hormone (TSH) level is
generally determined prior to starting a patient on an antidepressant,
as it is well known that abnormal TSH levels can cause various mental
health symptoms. As will be discussed in this article, consideration of
applicable research literature suggests that vitamin D levels should be
determined in patients who present with chronic pain, as there are
diverse pain syndromes that seem to occur in the presence of low vitamin
D levels.

Vitamin D deficiency in both adults and children has been
associated with numerous general health issues including type 1
diabetes, hypertension, metabolic syndrome, ischemic heart disease,
falls, broken bones, depression, and cancer.1-3 Recently,
vitamin D deficiency has been linked to chronic pain including pain with
sickle cell disease, aromatase inhibitor–induced arthralgia, leg pain
in older adults, headache, postherpetic neuralgia, pain in patients
taking high doses of opioids, symptomatic osteomalacia in gastric bypass
patients, diffuse bone and muscle pain, and chronic back pain.4-14
The case reviews and studies presented in this article suggest not only
an association of low vitamin D levels with various pain syndromes, but
also an improvement in symptoms with vitamin D repletion. Mechanisms
underlying this association have not been identified or quantified.

Vitamin D Absorption and Metabolism

The central role of vitamin D is to maintain normal blood
levels of calcium and phosphorous, thus helping to prevent osteoporosis
and reducing risk of fracture. The absorption and processing of vitamin D
is complex, with several influencers. Briefly, with sunlight exposure
7-dehydrocholesterol in the skin is converted to previtamin D3, which is thermally transformed to vitamin D3 (cholecalciferol).2 Vitamin D3 enters the circulation and is metabolized in the liver to 25-hydroxyvitamin D3
(25(OH)D3), which is converted in the kidney to 1, 25(OH)2D3. Serum
phosphorus and parathyroid hormone regulate renal production of 1,
25(OH)2D, which regulates calcium metabolism, as this form of vitamin D
interacts with its target organs—bone and intestine.2

Standardization of Serum Vitamin D Levels

Official parameters establishing levels of 25-hydroxyvitamin D (25(OH)D) were not established until 2011 (TABLE 1 illustrates current guidelines for determination of normal and abnormal vitamin D levels).15
In November 2010, the Institute of Medicine of the National Academies
released a report listing recommended daily allowance of vitamin D
assuming minimal sun exposure.15 North Americans need 600 IU
daily, with a maximum intake of 4,000 IU/day; however, persons over 70
years of age required 800 IU/day with a maximum of 4,000 IU daily.15
It is not clear at what dose vitamin D becomes toxic. Symptoms of
toxicity are due to hypercalcemia, which include nausea, vomiting,
muscle weakness, thirst, confusion, QT shortening, sinus tachycardia,
and headache.16 Persons with known hypercalcemia should avoid
vitamin D supplementation, and those with malabsorption syndrome should
be monitored closely for 25(OH)D, calcium, and phosphorus levels.

Repletion Modalities

Vitamin D is most commonly available OTC as cholecalciferol (D3). Ergocalciferol (D2)
is available in 50,000 IU capsules and by prescription. Repletion of
vitamin D levels requires replacement of serum 25(OH)D to normal levels
(i.e., >30 ng/mL). Dosing regimens vary depending on the severity of
depletion. For persons with 25(OH)D levels >20 ng/mL, 50,000 IU of D2 weekly for 6 to 8 weeks, followed by at least 800 IU of D3, should be given.17
For persons with 25(OH)D levels between 20 and 30 ng/mL, 800 IU may be
sufficient to achieve normal limit threshold of 25(OH)D. Monitoring
requires repeat 25(OH)D measurement every 3 to 4 months, with
adjustments as needed until levels are normalized.18

Review of Studies

Most of the studies and case reports included in this
review were done prior to the recent standards set for determining
normal, insufficient, and deficient vitamin D levels. Thus, this review
involves patients with various types of chronic pain; vitamin D
deficiency is reported with varying definitions of normal versus
abnormal vitamin D levels by researchers (TABLE 2).

In one case, a 16-year-old premenarcheal female with
sickle cell disease presenting with chronic pain, throbbing headaches,
nausea, and epigastric pain all unrelieved with nonsteroidal
anti-inflammatory drugs (NSAIDs), oral opioids, and other
multidisciplinary pain management strategies, was found to have a
vitamin D level of 7.9 ng/mL. She was treated with 50,000 IU of vitamin D
twice weekly, with 1,000 mg calcium carbonate (TUMS) added at week 4.
By week 14, her serum 25(OH)D was 30 ng/mL despite presumed occasional
noncompliance, and all pain symptoms were completely resolved.4

Breast cancer patients are often treated with an aromatase
inhibitor (AI). Resulting AI-associated arthralgias often lead to
nonadherence to therapy. Vitamin D levels were drawn on patients
receiving AI treatment (n = 290), and 90% were found to have vitamin D
levels <30 ng/mL, including 18.5% with baseline vitamin D levels of
<10 ng/mL.5 This study sought to determine a target
vitamin D level for alleviation of symptoms, finding that 40 ng/mL or
above alleviated symptoms. All participants received 800 IU of D3 with calcium daily. Participants with 25(OH)D levels <30 ng/mL received 800 IU of D3 plus 16,000 IU of D3
orally every 2 weeks. Nothing else was used to treat pain, compliance
was not monitored, and it is unknown if patients treated themselves with
OTC products. At 3 months, 50% of participants failed to reach adequate
vitamin D levels sufficient to alleviate incident pain. Appropriate
treatment dosing was determined to be too low, and further study was
recommended.5

In another case, an elderly woman complaining of
persistent all day and nighttime diffuse muscular aching pain (rated as 6
on a verbal analog scale of 0-10) was unrelieved with OTC medications.
Her 25(OH)D level was 15 ng/mL, and she was treated with 50,000 IU of
ergocalciferol for 8 weeks, with a significant decline in symptoms.6

Eight patients with tension headache presented with pain
described as over the entire head. Those with nearly continuous head
pain were found to have 25(OH)D levels of <10 ng/mL.7 When
questioned, patients also complained of easy fatigability and pain in
the low back, hip, and lower extremities. Conventional headache
treatments were not effective. All were treated with 1,000 to 1,500 IU
of D3 and 1,000 mg calcium daily, with complete resolution of
headache within 4 to 8 weeks. After 3 months, vitamin D levels had
normalized, followed by a marked decline in other symptoms.7

Glial inflammation in the central nervous system (CNS) and
Schwann cell activation in the peripheral nervous system (PNS)
influence pain; activation of the nervi nervorum in the PNS are thought
to be influencers of postherpetic neuralgia (PHN).8 Vitamin D
can reduce glial inflammation and nitric oxide production from Schwann
cell activation, which potentially could influence strategies for
reducing PHN pain. Although one patient with PHN and low vitamin D was
treated with vitamin D with a reduction in symptoms, vitamin D levels
and dosing for repletion were not described. Further studies are needed
to determine effectiveness of D repletion in patients affected by PHN.8,9

A retrospective study of 267 chronic pain patients in a
pain rehabilitation center found that 26% of patients had inadequate
levels of vitamin D. Patients with inadequate vitamin D were taking
nearly double the morphine equivalent dose taken by those with normal
levels of vitamin D (i.e., approximately 40 ng/day versus approximately
70 mg/day). It was not clear to the authors whether the morphine dose
caused low vitamin D levels or if higher doses of opioids were
prescribed to treat patients who happened to have low vitamin D levels.
Researchers felt that vitamin D inadequacy in this group might represent
an underrecognized influencer of nociception and impaired neuromuscular
function in chronic pain patients.10

Osteomalacia myopathy characterized by fatigue, muscle
aches, bone pain, and muscle weakness is frequently found in patients
who have undergone bariatric surgery, including gastric and jejunoileal
bypass.11,12 Two case report studies involved patients with
histories of either gastric bypass or jejunoileal bypass surgeries who
complained of the above symptoms and were found to be deficient in
vitamin D; in some cases vitamin D was undetectable. Repletion of
vitamin D and calcium over time resulted in symptom resolution.11,12

Several patients were thought to have a metastatic
malignancy and underwent imaging and laboratory studies and were
eventually found to have vitamin D deficiency. Repletion of vitamin D
and calcium over time resulted in symptom resolution.13

A case series of 6 patients with severe or disabling back
pain, and one patient with persistent back pain following failed back
surgery, were treated with 1,000 to 4,000 IU of cholecalciferol daily.
The results varied from improvement to complete resolution of pain
within 3 to 6 weeks.14

Summary of Studies

The studies discussed here considered numerous previous
investigations of various pain syndromes, their association with vitamin
D levels, and treatment with consistent dosing of ergocalciferol and/or
cholecalciferol (summarized in TABLE 2.) However, there remains a
paucity of current double-blind studies that consider the relationship
of these factors. Dosing required for vitamin D repletion based on
initial vitamin D levels needs to be investigated and guidelines
established. Treatment targets for achieving pain relief in multifarious
pain syndromes along with dosing guidelines require further
investigation. It is also important to know what types of pain syndromes
do not respond to vitamin D treatment. It is assumed that pain from
noxious stimuli, such as trauma and surgery, requires immediate relief
utilizing typical analgesics. However, further studies are required to
explore other pain syndromes that may or may not respond to vitamin D
treatment. It seems reasonable for primary care providers to screen for
vitamin D levels in their patients who report chronic pain, especially
when there is poor response to routine treatment. Similarly, it may be
reasonable for pharmacists to consider these relationships in counseling
patients who report inadequate or diminished efficacy of pain
medications.